Title: Fetal lipopolysaccharide exposure modulates diet-dependent gut maturation and sensitivity to necrotising enterocolitis in pre-term pigs Authors
|Cilieborg, Malene -|
|Schmidt, Mette -|
|Skovgaard, Kerstin -|
|Boye, Mette -|
|Weber, Nicolai -|
|Heegaard, Peter -|
|Sangild, Per -|
Submitted to: British Journal of Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: January 20, 2011
Publication Date: N/A
Interpretive Summary: Necrotising enterocolitis (NEC) is a devastating disease that occurs in premature infants. The growth of bacteria in the gut after birth is a critical factor that triggers NEC. Bacteria cause NEC more often in premature infants because they have an immature gut immune system that overreacts to bacteria. Previous studies suggested that causing a mild infection in utero, before birth, might help to induce maturation of the premature gut immune system and thus reduce the overreaction when bacteria begin to grow in the newborn gut after birth. We tested this idea by in utero injection of bacterial toxin, called LPS, intramuscularly or via amniotic fluid, a few days before birth and then feeding the premature piglets either formula or pig breast milk. We found that the incidence of NEC was higher in premature pigs fed formula vs. breast milk. We also found that premature pigs fed formula, but injected with LPS in the amniotic fluid in utero had a lower NEC incidence and improved intestinal function compared to those given only a placebo water injection. These results suggest that bacterial toxins given in utero can trigger a more mature gut immune response that reduces the risk of NEC. This approach may be useful if applied soon after birth to reduce the incidence of NEC in premature infants.
Technical Abstract: Uterine infections during pregnancy predispose to pre-term birth and postnatal morbidity, but it is unknown how prenatal bacterial exposure affects maturation of the immature gut. We hypothesised that a prenatal exposure to gram-negative lipopolysaccharide (LPS) has immunomodulatory effects that improve resistance towards necrotising enterocolitis (NEC) in pre-term neonates. At approximately 85 percent gestation, pig fetuses were injected intramuscularly with saline or LPS (0014 mg/kg), or intra-amniotically with LPS (04 mg/kg). Pigs were delivered by caesarean section 3–5 d later and fed colostrum (C) or formula (F) for 48 h. Gut indices did not differ between pigs injected intramuscularly with saline or LPS, and these groups were therefore pooled into two control groups according to diet (control-F, n 32 and control-C, n 11). Control-F pigs showed reduced villus heights, mucosal structure, gut integrity, digestive enzymes, elevated NEC incidence (38 v. 0 percent, P(005) and several differentially expressed immune-related genes, relative to control-C pigs. Compared with the control-F and control-C groups, values in formula-fed pigs given intra-amniotic LPS formula (n 17) were intermediate for villus height, enzyme activities, intestinal permeability and NEC incidence (18 percent, P=02 relative to control-F), and numbers of differentially expressed immune genes. In conclusion, prenatal exposure of the fetal gut to Gram-negative bacteria may modulate the immediate postnatal response to an enteral diet and colonising bacteria.